Why should intramuscular (IM) and intravenous (IV) promethazine be avoided?

Why IM and IV Promethazine Should Be Avoided

The shift away from IM and IV promethazine is driven by well-documented risks of severe tissue injury—including thrombophlebitis, tissue necrosis, and gangrene—that can occur with both routes, coupled with the availability of safer alternatives and recognition that lower oral doses are equally effective. 1, 2, 3

Primary Safety Concerns by Route

Intravenous Administration Risks

IV promethazine carries significant tissue injury risks:

• Thrombophlebitis and vascular damage occur even with proper IV administration, as promethazine is highly caustic to the intima of blood vessels 3, 4
• Extravasation can cause tissue necrosis and gangrene, representing limb-threatening complications that have been documented for decades 1, 2, 3
• Inadvertent intra-arterial injection results in severe vascular injury and potential limb loss 3, 4
• The FDA acted in December 2023 to change product labeling, now stating a preference for intramuscular over intravenous administration due to these tissue injury risks 3

Intramuscular Administration Risks

IM promethazine is not without serious complications:

• Abscess formation and tissue necrosis have been documented with IM administration, including cases of methicillin-sensitive Staphylococcus aureus bacteremia requiring 6 weeks of IV antibiotics 5
• Unpredictable absorption from IM depot injections can result in erratic effects, particularly problematic in unstable patients 6
• The deltoid or vastus lateralis muscles are preferred sites if IM administration is necessary, but this does not eliminate tissue injury risk 7

Systemic Safety Issues Common to Both Routes

Beyond local tissue injury, parenteral promethazine poses systemic risks:

• Respiratory depression increases with cumulative dosing and is particularly dangerous when combined with opioids 1, 8
• Significant sedation occurs with standard 25 mg doses, especially problematic in combination with narcotics 1, 9
• Hypotension risk requires slow IV infusion (≤25 mg/min) if this route is used 1, 2
• Extrapyramidal effects including neuroleptic malignant syndrome can occur, making chronic use inappropriate 1

Evidence Supporting Oral Administration

Oral promethazine is equally effective and substantially safer:

• Lower oral doses (6.25-12.5 mg) provide equivalent antiemetic efficacy to IV ondansetron 4 mg, with 74% relief at one hour for 6.25 mg promethazine versus 59% for ondansetron 9
• The American Academy of Pediatrics notes oral administration is equivalent to parenteral if GI absorption is intact 1
• Oral bioavailability is 25%, yet current evidence shows lower doses are therapeutically sufficient 1, 9
• The American Gastroenterological Association recommends oral or rectal promethazine 12.5-25 mg every 4-6 hours as first-line therapy for nausea and vomiting 1

Clinical Practice Implications

When parenteral administration seems necessary:

1. Reconsider the route: Oral or rectal administration should be attempted first unless contraindicated 1
2. If IV is unavoidable: Use large, patent veins; dilute the medication; infuse slowly (≤25 mg/min); and never exceed 25 mg per dose 2, 3, 4
3. Prefer IM over IV: The FDA now recommends IM as the preferred parenteral route, using deep injection into deltoid or vastus lateralis 7, 3
4. Consider alternatives: Ondansetron, metoclopramide, or other antiemetics with safer profiles should be evaluated 5, 9

Common Pitfalls to Avoid

• Using standard 25 mg doses when lower doses suffice: Evidence shows 6.25-12.5 mg IV is equally effective with less sedation 9
• Administering through small or questionable IV access: This increases extravasation risk 4
• Combining with opioids without dose adjustment: This combination significantly increases respiratory depression risk 1
• Repeated or prolonged parenteral courses: Cumulative tissue injury risk makes this particularly dangerous 1, 2

Patient safety organizations have called for hospitals to remove injectable promethazine from formularies entirely, reflecting the severity of documented adverse events and availability of safer alternatives 3